Ketamine and Etomidate Down-regulate the Hypothalamic-Pituitary-Adrenal Axis in an Endotoxemic Mouse Model.

BACKGROUND: We compared the effects of etomidate and ketamine on the hypothalamic-pituitary-adrenal axis during sepsis. METHODS: Mice (n = 5/group) were injected intraperitoneally with lipopolysaccharide (10 mg/kg) and 6 h later randomized to receive ketamine (100 mg/kg), etomidate (30 mg/kg), or saline. At two time points (12 and 48 h), messenger RNA levels of hypothalamic corticotropin-releasing hormone, pituitary proopiomelanocortin, and four adrenal enzymes (P450 side-chain cleavage, 3ß-hydroxysteroid deshydrogenase, 21-hydroxylase, and 11ß-hydroxylase) were measured by in situ hybridization (results are presented as optical density), and plasma levels of corticosterone and adrenocorticotropin hormones were measured by enzyme-linked immunosorbent assay (mean ± SD). RESULTS: At 12 h, lipopolysaccharide induced an overexpression of corticotropin-releasing hormone (32 ± 5 vs. 18 ± 6, P < 0.01), proopiomelanocortin (21 ± 3 vs. 8 ± 0.9, P < 0.0001), P450 side-chain cleavage (32 ± 4 vs. 23 ± 10, P < 0.05), 21-hydroxylase (17 ± 5 vs. 12 ± 2, P < 0.05), and 11ß-hydroxylase (11 ± 4 vs. 6 ± 0.5, P = 0.001), and an elevation of corticosterone (642 ± 165 vs. 98.3 ± 63 ng/ml, P < 0.0001). Etomidate and ketamine reduced P450 side-chain cleavage (19 ± 7 and 19 ± 3 vs. 32 ± 4, P < 0.01), 21-hydroxylase (8 ± 0.8 and 8 ± 1 vs. 17 ± 5, P < 0.001), 11ß-hydroxylase (4 ± 0.5 and 7 ± 1 vs. 11 ± 4, P < 0.001 and P < 0.05), and corticosterone (413 ± 189 and 260 ± 161 vs. 642 ± 165 ng/ml, P < 0.05 and P < 0.01). Ketamine also inhibited adrenocorticotropin hormone production (2.5 ± 3.6 vs. 36 ± 15 pg/ml, P < 0.05). At 48 h, all four adrenal enzymes were down-regulated by lipopolysaccharide administration with corticosterone levels similar to the control group. Ketamine and etomidate did not modify corticosterone plasma levels. CONCLUSIONS: Our endotoxemic model induces an initial activation of the hypothalamic-pituitary-adrenal axis, followed by a secondary inhibition of adrenal steroidogenesis processes. Ketamine and etomidate inhibit the enzyme expression and activity of the adrenal gland at the early stage.

Unrepaired Tetralogy of Fallot-related Pathophysiologic Changes Reduce Systemic Clearance of Etomidate in Children.

BACKGROUND: Pathophysiologic changes in children with congenital heart disease may alter the effect of drugs by influencing the pharmacokinetics (PK). Considering the limited literature that describes the PK of etomidate in pediatric patients, especially in those with tetralogy of Fallot (TOF), our aim was to characterize the PK of etomidate and explore the effects of TOF. METHODS: Twenty-nine pediatric patients (15 with TOF and 14 with normal cardiac anatomy) scheduled to undergo elective surgery under general anesthesia were recruited in the study. All children received etomidate 60 µg/kg/min intravenously until a bispectral index of ≤50 was reached for 5 seconds during anesthesia induction. Arterial blood samples were drawn and analyzed. Population analysis was performed by using NONMEM to define PK characteristics. The estimates were standardized to a 70-kg adult using a per-kilogram model. RESULTS: Data consisting of 244 samples from 29 children with a mean age of 236 days (range, 86-360 days) were used, including a TOF group with a mean age of 250 days (range, 165-360 days) and a normal cardiac anatomy group with a mean age of 221 days (range, 86-360 days). A 3-compartment disposition model was best fitted to describe the PK of etomidate. The introduction of TOF as a covariate for systemic clearance (Cl1) improved the model and resulted in a significant reduction of objective function (Δobjective function = -7.33; P = .0068), which means that TOF was a significant covariate of Cl1, and the etomidate Cl1 in children with TOF (1.67 × (weight [WT]/70 kg) L/min) was lower than those with normal cardiac anatomy (2.28 × (WT/70 kg) L/min). Other PK parameter values were as follows: V1 = 8.05 × (WT/70 kg) L; V2 = 13.7 × (WT/70 kg) L; V3 = 41.3 × (WT/70 kg) L; Cl2 = 3.35 × (WT/70 kg) L/min; Cl3 = 0.563 × (WT/70 kg) L/min. CONCLUSIONS: A decreased systemic clearance for etomidate in children with TOF resulted in a lower required infusion rate and variation with time to achieve the same plasma concentration and maintain an equivalent target concentration or have longer sedation and recovery times after bolus or continuous infusion than normal children.

Haematological effects of 2-phenoxyethanol and etomidate in carp (Cyprinus carpio L.).

OBJECTIVE: To evaluate the effects of handling alone versus handling under anaesthesia with 2-phenoxyethanol or etomidate on haematological parameters in carp. STUDY DESIGN: Prospective, randomized, laboratory experiment. ANIMALS: Seventy-two juvenile carp (Cyprinus carpio) weighing 35.9 ± 10.4 g were divided into six groups of 12 fish. METHODS: Either 2-phenoxyethanol or 2% etomidate were administered to induce deep anaesthesia (0.3 mL L(-1) and 0.6 mL L(-1) , respectively) or deep sedation (0.15 mL L(-1) and 0.3 mL L(-1) , respectively). Fish were handled with and without sedation. Blood was sampled at 1 hour and 1 week post-treatment. Phagocyte oxidative activity [nitrotetrazolium blue reduction test (NBT)] and differential erythrocyte [red blood cell (RBC)] and leukocyte (white blood cell) counts were evaluated. RESULTS: At 1 hour after the induction of anaesthesia, haematocrit (Ht) and haemoglobin (Hb) were increased in fish anaesthetized with 2-phenoxyethanol, and mean corpuscular haemoglobin (MCH) was increased in fish anaesthetized with etomidate. At 1 week, an increase in RBC, erythroblastosis, erythrocyte damage, lymphopenia, neutrophilia, monocytosis and thrombocytosis occurred in both groups. Red blood parameters did not change 1 hour after handling alone, but after 1 week Ht, Hb and mean cell volume decreased, whereas MCH concentration (MCHC) and abnormal erythrocytes increased. Lymphopenia, neutrophilia, monocytosis, thrombocytosis and a decrease in NBT occurred. Fish handled under sedation showed an increase in Hb and MCHC followed by a decrease at 1 week in Ht, Hb and MCH, erythroblastosis and increased abnormal erythrocytes. Lymphopenia and neutrophilia were less pronounced than in fish handled without sedation, but a decrease in NBT was noted at 1 week post-treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Deep anaesthesia with 2-phenoxyethanol or etomidate induced significant haematological alterations in juvenile carp. Deep sedation reduced the immediate immunosuppressive effects of handling but did not eliminate longterm effects. These anaesthetics should be avoided during experimental procedures involving haematological measurements. In contexts that require the short-term handling of carp, these drugs should be used with caution in view of their possible side effects.

In vivo and in vitro pharmacological studies of methoxycarbonyl-carboetomidate.

BACKGROUND: We previously developed 2 etomidate analogs that retain etomidate's favorable hemodynamic properties but whose adrenocortical effects are reduced in duration or magnitude. Methoxycarbonyl (MOC)-etomidate is rapidly metabolized and ultrashort acting whereas (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate) does not potently inhibit 11ß-hydroxylase. We hypothesized that MOC-etomidate's labile ester could be incorporated into carboetomidate to produce a new agent that possesses favorable properties individually found in each agent. We describe the synthesis and pharmacology of MOC-(R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (MOC-carboetomidate), a "soft" analog of carboetomidate. METHODS: MOC-carboetomidate's octanol:water partition coefficient was determined chromatographically and compared with those of etomidate, carboetomidate, and MOC-etomidate. MOC-carboetomidate's 50% effective concentration (EC(50)) and 50% effective dose for loss of righting reflexes (LORR) were measured in tadpoles and rats, respectively. Its effect on γ-aminobutyric acid A (GABA(A)) receptor function was assessed using 2-microelectrode voltage clamp electrophysiological techniques and its metabolic stability was determined in pooled rat blood using high performance liquid chromatography. Its duration of action and effects on arterial blood pressure and adrenocortical function were assessed in rats. RESULTS: MOC-carboetomidate's octanol:water partition coefficient was 3300 ± 280, whereas those for etomidate, carboetomidate, and MOC-etomidate were 800 ± 180, 15,000 ± 3700, and 190 ± 25, respectively. MOC-carboetomidate's EC(50) for LORR in tadpoles was 9 ± 1 µM and its EC(50) for LORR in rats was 13 ± 5 mg/kg. At 13 µM, MOC-carboetomidate enhanced GABA(A) receptor currents by 400% ± 100%. Its metabolic half-life in pooled rat blood was 1.3 min. The slope of a plot of the duration of LORR in rats versus the logarithm of the hypnotic dose was significantly shallower for MOC-carboetomidate than for carboetomidate (4 ± 1 vs 15 ± 3, respectively; P = 0.0004123). At hypnotic doses, the effects of MOC-carboetomidate on arterial blood pressure and adrenocortical function were not significantly different from those of vehicle alone. CONCLUSIONS: MOC-carboetomidate is a GABA(A) receptor modulator with potent hypnotic activity that is more rapidly metabolized and cleared from the brain than carboetomidate, maintains hemodynamic stability similar to carboetomidate, and does not suppress adrenocortical function.

Fast and reliable analysis of veterinary metomidate and etomidate in human blood samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in a postmortem case.

Metomidate and etomidate belong to the non-barbiturate imidazole family of sedative-hypnotics and elicit little analgesic action when used alone. Metomidate, in particular, has little analgesic activity in humans and is, therefore, used for veterinary purposes. In 2019, a Korean woman in her twenties was found unconscious in a motel bath and eventually died. Etomidate, alprazolam, escitalopram, and metomidate were detected in the postmortem specimens. To our knowledge, this is the first case of human metomidate abuse reported in the Republic of Korea. In this research, a simple and reliable method was developed for the analysis of metomidate and etomidate in human blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Blood samples were deproteinized with acetonitrile, filtered, and analyzed by LC-MS/MS. Linear calibration curves were obtained with six concentrations ranging from 1 to 50 ng/ml for metomidate and 10 to 500 ng/ml for etomidate. The method was validated by assessing the selectivity, linearity, limit of detection (LOD), limit of quantitation (LOQ), intra- and inter-day precision and accuracy, matrix effect, and stability and successfully applied to the analysis of metomidate and etomidate in human blood samples. In a postmortem case, the concentrations of metomidate and etomidate were found to be 8 and 110 ng/ml in femoral blood and 6 and 210 ng/ml in cardiac blood, respectively.

Application of petal-shaped ionic liquids modified covalent organic frameworks for one step cleanup and extraction of general anesthetics in human plasma samples.

Here, the novel petal-shaped ionic liquids modified covalent organic frameworks (PS-IL-COFs) particles have been synthesized by using ionic liquids as modifying agent, which could be beneficial to avoid the aggregation of COFs during the preparation and improve its dispersing performance. The novel PS-IL-COFs particles have been used and evaluated in the one step cleanup and extraction (OSCE) procedure for human plasma prior to the analysis of 3 general anesthetics by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). In the OSCE procedure, human plasma samples are directly mixed with extraction solvent and PS-IL-COFs particles, and the extraction and cleanup procedure have been carried out simultaneously. Compared with the Oasis PRiME HLB cartridge method, the OSCE procedure using PS-IL-COFs particles as sorbents is much more effective for the minimization of ion suppression resulted from blood phospholipids. Under optimal conditions, the PS-IL-COFs particles show higher cleanup efficiency of 3 general anesthetics with recoveries in the range of 82.5%-115%. The limits of quantification (LOQs) for propofol, ketamine and etomidate are 0.18 µg/L, 0.15 µg/L and 0.016 µg/L, respectively. Validation results on linearity, specificity, precision and trueness, as well as on the application to analysis of general anesthetics in a case of a 54-year-old female suffered gallstone demonstrate the applicability to clinical studies.

Preclinical Pharmacokinetics Study of a Novel Intravenous Anesthetic ET-26 Hydrochloride.

BACKGROUND: ET-26 hydrochloride is a novel intravenous anesthetic, approved for clinical trials, that produces a desirable sedative-hypnotic effect with stable myocardial performance and mild adrenocortical suppression in rats and beagle dogs. The objective of this study was to assess the absorption, distribution, metabolism, and excretion of ET-26 hydrochloride. METHODS: Hepatocytes from human, monkey, dog, rat, and mouse were used to determine the metabolites of ET-26 hydrochloride. Distribution and excretion were assessed in rats and pharmacokinetic studies were performed in beagle dogs. RESULTS: The metabolic pathway and proposed structure of metabolites were fully assessed resulting from the biotransformation reactions of hydrolysis, dehydrogenation, demethylation and glucuronic acid conjugation. The main distribution of the drug was in fat (15067 ± 801 ng/ml) and liver (13647 ± 1126 ng/ml), and the kidney was the primary excretion route (4.47%-11.94%). The Cmax after injection with 1.045 mg/kg, 2.09 mg/kg, and 4.18 mg/kg was 1476.5 ± 138.9 ng/ml, 2846.1 ± 223.3 ng/ml, and 6233.3 ± 238.9 ng/ml, respectively. The t1/2 of the drug was similar across dose groups at 74.8 ± 10.8 min to 81.4 ± 4.2 min. The AUC0-t values were 30208.1 ± 2026.5 min*ng/ml, 62712.8 ± 1808.3 min*ng/ml, and 130465.2 ± 7457.4 min*ng/ml, respectively. CONCLUSION: The metabolic pathway and the proposed structure of metabolites for ET-26 hydrochloride were fully assessed. The majority of distribution for ET-26 hydrochloride occurs in the fat and liver, while the primary route of excretion for ET-26 hydrochloride is through the kidney. In dogs, pharmacokinetic features of ET-26 hydrochloride had a linear relationship with dosage.

Effect of etomidate and propofol induction on hemodynamic and endocrine response in patients undergoing coronary artery bypass grafting/mitral valve and aortic valve replacement surgery on cardiopulmonary bypass.

INTRODUCTION: The concerns for induction of anaesthesia in patients undergoing cardiac surgery include hemodynamic stability, attenuation of stress response and maintenance of balance between myocardial oxygen demand and supply. Various Intravenous anaesthetic agents like Thiopentone, Etomidate, Propofol, Midazolam, and Ketamine have been used for anesthetizing patients for cardiac surgeries. However, many authors have expressed concerns regarding induction with thiopentone, midazolam and ketamine. Hence, Propofol and Etomidate are preferred for induction in these patients. However, these two drugs have different characteristics. Etomidate is preferred for patients with poor left ventricular (LV) function as it provides stable cardiovascular profile. But there are concerns about reduction in adrenal suppression and serum cortisol levels. Propofol, on the other hand may cause a reduction in systemic vascular resistance and subsequent hypotension. Thus, this study was conducted to compare induction with these two agents in cardiac surgeries. METHODS: Baseline categorical and continuous variables were compared using Fisher's exact test and student's t test respectively. Hemodynamic variables were compared using student's t test for independent samples. The primary outcome (serum cortisol and blood sugar) of the study was compared using Wilcoxon Rank Sum test. The P value less than 0.05 was considered significant. RESULTS: Etomidate provides more stable hemodynamic parameters as compared to Propofol. Propofol causes vasodilation and may result in drop of systematic BP. Etomidate can therefore be safely used for induction in patients with good LV function for CABG/MVR/AVR on CPB without serious cortisol suppression lasting more than twenty-four hours.

Imaging of adrenal incidentalomas with PET using (11)C-metomidate and (18)F-FDG.

UNLABELLED: Our aim was to evaluate the use of PET with (11)C-metomidate and (18)F-FDG for the diagnosis of adrenal incidentalomas. METHODS: Twenty-one patients underwent hormonal screening before dynamic imaging of the upper abdomen with (11)C-metomidate, and for 19 of these 21 patients, static (18)F-FDG imaging followed. Uptake of (11)C-metomidate and (18)F-FDG in incidentalomas was quantified and correlated with the hormonal work-up and the mass size on CT (median, 2.5 cm; range, 2-10 cm). RESULTS: The final diagnoses were hormonally active adenoma (n = 7), nonsecretory adenoma (n = 5), adrenocortical carcinoma (n = 1), pheochromocytoma (n = 2), benign noncortical tumor (n = 2), normal adrenal (n = 1), and malignant noncortical tumor (n = 3). Diagnosis was established at surgery (n = 9), percutaneous biopsy (n = 4), or follow-up (n = 8). The highest uptake of (11)C-metomidate, expressed as standardized uptake value (SUV), was found in adrenocortical carcinoma (SUV = 28.0), followed by active adenomas (median SUV = 12.7), nonsecretory adenomas (median SUV = 12.2), and noncortical tumors (median SUV = 5.7). Patients with adenomas had significantly higher tumor-to-normal-adrenal (11)C-metomidate SUV ratios than did patients with noncortical tumors. (18)F-FDG detected 2 of 3 noncortical malignancies but failed to detect adrenal metastases from renal cell carcinoma. All inactive and most active adenomas were difficult to detect with (18)F-FDG against background activity, whereas both pheochromocytomas and adrenocortical carcinoma showed slightly increased uptake of (18)F-FDG. There was no correlation between uptake of (11)C-metomidate or (18)F-FDG and mass size. CONCLUSION: (11)C-Metomidate is a promising PET tracer to identify incidentalomas of adrenocortical origin. (18)F-FDG should be reserved for patients with a moderate to high likelihood of neoplastic disease.

Plasma protein binding of etomidate in patients with renal failure or hepatic cirrhosis.

The influence of renal failure and of hepatic cirrhosis on the plasma protein binding of etomidate, an intravenous anaesthetic agent of basic nature, has been investigated. The percentage of free etomidate in plasma containing 1 microgram/ml was markedly increased in patients with renal failure and in patients with hepatic cirrhosis, when compared with a group of healthy volunteers (43.4 +/- 2.9% and 44.2 +/- 2.1 versus 24.9 +/- 1.4%). This decrease in binding correlated inversely with serum albumin levels in both conditions (r = -0.88 and r = 0.72, respectively) but a slight decrease in the amount bound per mole of albumin was also apparent in both types of disease.

Etomidate-anaesthesia, with and without fentanyl, compared with urethane-anaesthesia in the rat.

In spontaneously breathing rats, continuous infusion of etomidate with and without fentanyl caused a slight decrease in blood pressure and heart rate. Coadministration of fentanyl and etomidate in order to obtain full anaesthesia and analgesia resulted in respiratory depression. In artificially ventilated rats both etomidate as well as the anaesthetic combination caused a strong reduction in aortic flow and an increase in total peripheral resistance. A single infusion of etomidate did not change blood pressure. Etomidate combined with fentanyl reduced blood pressure. Under adjusted ventilation blood pressure, aortic flow, max(dF/dt) and heart rate were progressively reduced during a 4 h period. In contrast, urethane anaesthesia reduced aortic flow to a minor extent. Total peripheral resistance and max(dF/dt) were hardly affected. The slightly reduced blood pressure and blood gas variables remained stable during the experiment. From pharmacokinetic studies it was established that effective etomidate plasma levels were maintained constant during the experimental period. Pharmacokinetic interaction between etomidate and fentanyl did not occur. It is concluded that for anaesthesia of longer duration during cardiovascular experiments in rats, urethane is preferable to etomidate/fentanyl because it does not cause serious changes in basal haemodynamic variables.

Adrenocortical suppression and other endocrine effects of etomidate.

(+/-) Etomidate is a short-acting general anaesthetic given by the intravenous route. It has strong adrenal suppression capability initially shown in the rat and then observed in man. At present, the drug seems the most effective adrenocortical inhibitor on a molar basis in vitro. 11 beta-hydroxylase is the most sensitive target enzyme; 16 alpha-, 17 alpha-hydroxylase and cholesterol side-chain cleavage are inhibited by higher concentrations. (+) Etomidate was more active than the (+/-) and far more than the (-) stereoisomer. Etomidate blood concentrations greatly exceed those needed to block adrenal steroidogenesis both when used inappropriately by infusion for long-term sedation (such previously unrecognized drug-induced adrenal suppression has often proved fatal in severely-injured patients) and also when given in very low doses as an induction anaesthetic. Reactive ACTH increase is currently observed. Etomidate, in vivo, does not appear to affect testicular steroidogenesis although it shares an imidazole moiety with fungicide phenylimidazoles endowed with such an action. However, testosterone production may be reduced by high concentrations in vitro. Other gonadal hormones seem unchanged. Both basal and stress-induced blood prolactin levels are lowered by etomidate in the rat but probably not in man arguably through interference at brain level where the GABA-benzodiazepine receptor complex could be directly involved. Hence, endocrine and neuroendocrine interferences are unique non-anaesthetic effects of etomidate.

High-performance liquid chromatographic assay for etomidate in human plasma: results of preliminary clinical studies using etomidate for hypnosis in total intravenous anesthesia.

A sensitive and specific high-performance liquid chromatographic assay was developed for the measurement of etomidate in human plasma following extraction of the drug and the internal standard. Using 0.5-ml aliquots of plasma, the assay was linear in the concentration range of 20-2000 ng of etomidate/ml of plasma. This method was used to evaluate a preliminary clinical study of an etomidate infusion regimen for hypnosis in a total intravenous anesthesia protocol in 23 patients. The average duration of the infusion was 30 min, and awakening and alertness occurred 20 and 36 min after the termination of the infusion, respectively, at the respective plasma concentrations of 297 and 214 ng/ml. These results and this assay will be used to design and evaluate an improved etomidate infusion regimen.

Mass fragmentographic determination of plasma etomidate concentrations.

The intravenous anesthetic etomidate was measured in human plasma by mass fragmentography. The method is accurate, sensitive, and specific. Results of the analyses indicate that after a single 0.3-mg/kg iv dose of etomidate, there are at least three phases in its disappearance from human plasma. Detectable plasma concentrations exist for more than 6 hr after injection.

A simple and efficient high-performance liquid chromatographic assay for etomidate in plasma.

The development and validation of an effective and simplified LC assay for the quantitation of etomidate in beagle plasma is described. The methodology employs a rapid and simple protein precipitation procedure in combination with previously reported chromatographic conditions. Using a 0.3 ml aliquot of plasma, the assay is linear in the concentration range of 50 to 5000 ng/ml, with an extraction efficiency between 97 to 104% and accuracy between 98 and 105%.

Pharmacokinetics of etomidate in cats.

Pharmacokinetic variables of etomidate were determined after IV administration of etomidate (3.0 mg/kg of body weight). Blood samples were collected for 6 hours. Disposition of this carboxylated imidazole best conformed to a 2- (n = 2) and a 3- compartment (n = 4) open pharmacokinetic model. The pharmacokinetic values were calculated for the overall best-fitted model, characterized as a mixed 2- and 3-compartmental model. The first and most rapid distribution half-life was 0.05 hour and a second distribution half-life was 0.35 hour. Elimination half-life was 2.89 hours, apparent volume of distribution was 11.87 +/- 4.64 L/kg, apparent volume of distribution at steady state was 4.88 +/- 2.25 L/kg, apparent volume of the central compartment was 1.17 +/- 0.70 L/kg, and total clearance was 2.47 +/- 0.78 L/kg/h.

Duration of etomidate-induced adrenocortical suppression during surgery in dogs.

Plasma cortisol concentrations were compared in canine surgical patients given etomidate (2 mg/kg of body weight, IV) or thiopental sodium (12 mg/kg, IV) for anesthetic induction. Blood samples to determine plasma concentrations of etomidate were obtained at 0, 5, 10, 15, and 30 minutes and 1, 2, 3, 4, 5, 6, 8, 12, and 24 hours after induction. Adrenocortical function was evaluated before surgery by use of adrenocorticotropic hormone stimulation tests. Dogs in both induction groups had high plasma cortisol concentrations after induction. Dogs given thiopental had a significant increase (P less than 0.05) in plasma cortisol concentration from baseline at 2, 3, 4, 5, 6, 8, and 12 hours after induction. Dogs given etomidate had a significant increase (P less than 0.05) in plasma cortisol concentration from baseline at 5, 6, and 8 hours after induction. A comparison of plasma cortisol concentrations determined at 2, 3, 4, 5, and 6 hours after induction with thiopental or etomidate revealed a higher (P less than 0.05) concentration in dogs given thiopental. The disposition of etomidate was best described by a 2-compartment model, with a redistribution half-life of 0.12 +/- 0.04 minute and a terminal half-life of 1.70 +/- 0.27 minute. Plasma cortisol concentrations did not correlate with plasma etomidate concentrations. We conclude that, compared with thiopental, a single bolus injection of etomidate reduces the adrenocortical response to anesthesia and surgery from 2 to 6 hours after induction. Because cortisol concentrations were significantly higher than baseline, and because cardiopulmonary function is maintained after a single bolus injection of etomidate, it can be considered a safe induction agent in dogs.

A rapid method of determining serum levels of etomidate by gas chromatography with the aid of a nitrogen detector.

A rapid method of measuring etomidate in serum is described which is suitable for the determination of serum levels during and after surgical procedures. Etomidate with the added internal standard propoxate is extracted from serum using a hexane/ether mixture. The organic layer is evaporated and the residue dissolved in acetone and injected into an OV-17 column at 220 degrees C. Resulting concentrations are linear between 0.05 and 2.0 microgram/ml serum. There is 90% recovery and the detection limit is 0.03 microgram/ml. The other drugs normally present do not interfere with the estimation. Estimations can be carried out on 20 blood samples by one person with 3 hours.

Plasma levels of alfentanil and etomidate in patients and their relation to compressed power spectral analysis of the EEG.

In 22 patients alfentanil-etomidate anesthesia was used for orthopedic procedures using for the induction period 300 micrograms/kg of the hypnotic and 100 micrograms/kg of the opioid. Maintenance of anesthesia consisted of 20 micrograms/kg of alfentanil given every 15 min and 20 micrograms/kg/min of etomidate given over an infusion. The patients were intubated and mechanically ventilated with pure oxygen. In order to access the state of vigilance with respect to etomidate and alfentanil plasma levels, EEG power spectra were computed from electrical cortical activity of the occipital region (P3-O1); respectively venous blood samples were assayed by means of gas chromatography for alfentanil and etomidate plasma concentration. In the EEG power spectrum, anesthesia replaced the high dominant alpha-peaks of the control-awake period by a disharmonious pattern over the whole frequency range (0.5-16.0 Hz). At the end of anesthesia vigilance recording indicated a correlation with plasma etomidate level. Once concentration had dropped below 100 ng/ml power spectra were characterized by a stable harmonious peak in the alpha-range (8.0-10.0 Hz). Plasma levels above 100 ng/ml induced a fluctuating pattern with peaks in the theta to delta band (0.5-8.0 Hz); the latter was characterized by drowsiness and a reduced respiratory drive. Opioid plasma levels above 100 ng/ml with etomidate levels below 80 ng/ml did not influence to the same extent. EEG power spectra seem to be a useful tool in pinpointing to a reduced state of vigilance. Such a state when present with opioid ingestion is often accompanied by respiratory depression.